NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp) AND Houge-Janssens syndrome 2

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Dec 3, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000170500.17

Allele description [Variation Report for NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp)]

NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp)

Gene:

PPP2R1A:protein phosphatase 2 scaffold subunit Aalpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.41

Genomic location:

Preferred name:

NM_014225.6(PPP2R1A):c.544C>T (p.Arg182Trp)

HGVS:

NC_000019.10:g.52212726C>T
NG_047068.1:g.27925C>T
NM_001363656.2:c.7C>T
NM_014225.6:c.544C>TMANE SELECT
NP_001350585.1:p.Arg3Trp
NP_055040.2:p.Arg182Trp
NC_000019.9:g.52715979C>T
NM_014225.5:c.544C>T
NR_033500.2:n.488C>T
P30153:p.Arg182Trp

Protein change:

R182W; ARG182TRP

Links:

UniProtKB: P30153#VAR_074489; OMIM: 605983.0001; dbSNP: rs786205227

NCBI 1000 Genomes Browser:

rs786205227

Molecular consequence:

NM_001363656.2:c.7C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014225.6:c.544C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_033500.2:n.488C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Houge-Janssens syndrome 2
Synonyms:: Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome; INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 36
Identifiers:: MONDO: MONDO:0014605; MedGen: C4225352; Orphanet: 457284; OMIM: 616362

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222932	OMIM	no assertion criteria provided	Pathogenic (Aug 3, 2015)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25533962, 26168268
SCV000680347	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 8, 2017)	de novo	clinical testing	Citation Link,
SCV000893541	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001429604	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2019)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001445875	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002547295	GenomeConnect - Brain Gene Registry	no classification provided	not provided	de novo	phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	de novo	yes	2	not provided	not provided	1	not provided	clinical testing, phenotyping only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study..

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.

PubMed [citation]

PMID:: 25533962
PMCID:: PMC5955210

Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M, Vogt J, McKee S, Tolmie JL, Cordeiro N, Kleefstra T, Willemsen MH, Reijnders MR, Berland S, Hayman E, Lahat E, Brilstra EH, van Gassen KL, Zonneveld-Huijssoon E, de Bie CI, Hoischen A, Eichler EE, et al.

J Clin Invest. 2015 Aug 3;125(8):3051-62. doi: 10.1172/JCI79860. Epub 2015 Jul 13.

PubMed [citation]

PMID:: 26168268
PMCID:: PMC4623570

See all PubMed Citations (3)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000222932.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 unrelated girls with Houge-Janssens syndrome-2 (HJS2; 616362), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-T transition at chromosome coordinate g.52,715,979 (chr19.52,715,979C-T, GRCh37) in the PPP2R1A gene, resulting in an arg182-to-trp (R182W) substitution. This mutation occurred as a de novo event in both patients. No functional studies were performed.

In a patient with MRD36, Houge et al. (2015) identified a de novo heterozygous c.544C-T transition (c.544C-T, NM_014225.5) in the PPP2R1A gene that resulted in a R182W substitution.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893541.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429604.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was identified as de novo (maternity and paternity confirmed).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445875.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been previously reported as a de novo change in multiple patients with intellectual disability, agenesis of the corpus callosum, and dysmorphic facies (PMID: 25533962, 26168268, 28628100). Cellular binding assays revealed that p.Arg182Trp affected PP2A holoenzyme formation, dephosphorylation dynamics, and link PP2A dysfunction to congenital brain dysfunction (PMID: 26168268). The variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. ClinVar contains an entry for the variant (Variation ID: 190312). The c.544C>T (p.Arg182Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.544C>T (p.Arg182Trp) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect - Brain Gene Registry, SCV002547295.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 08-12-2019 by lab or GTR ID 26957. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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